Intramolecular hydroamidation of alkenes enabling asymmetric synthesis of β-lactams via transposed NiH catalysis

Abstract

Synthetic methods for constructing enantioenriched β-lactams are highly valuable given their ubiquity in bioactive compounds, most notably in antibiotics such as penicillins and carbapenems. Intramolecular hydroamidation of β,γ-unsaturated amides would provide a convenient means to reach this alluring chemical space, yet it remains limited due to the regioselectivity issue arising from the difficulty associated with the formation of strained four-membered rings. Here we describe a NiH-catalysed strategy that addresses this challenge through the use of readily accessible alkenyl dioxazolone derivatives. The reaction transcends the conventional NiH operation mode via a transposed mechanism initiated by N-activation, thus allowing for proximal C–N bond formation with excellent regioselectivity, regardless of the electronic properties of substituents. This mechanistic platform is also highly effective for the enantioselective intramolecular hydroamidation of alkenes to enable a convenient access to enantioenriched β-lactams. Strategies for the asymmetric synthesis of β-lactams are highly sought after. Now, a NiH-catalysed enantioselective intramolecular hydroamidation of alkenes affording β-lactam scaffolds is described, whereby the C–N bond is formed with unusual regioselectivity at the more proximal position.